It has recently been determined that HIV protease inhibiting compounds are useful for inhibiting HIV protease in vitro and in vivo and are also useful for inhibiting an HIV (human immunodeficiency virus) infection.
It has also recently been determined that compounds of the formula I: ##STR1## wherein R.sub.1 is loweralkyl and R.sub.2 and R.sub.3 are phenyl are particularly useful as inhibitors of HIV protease and are useful for inhibiting HIV protease in vitro and in vivo and are also useful to inhibit HIV infections.
In particular, the compound of formula II has been found to be especially effective as an inhibitor of HIV-1 protease. ##STR2##
Particularly useful in the preparation of compound of formula is a compound of formula III. ##STR3##
The preparation of compounds II and III and the use of compound of as an inhibitor of HIV protease are disclosed in PCT Patent Application No. WO94/14436, published Jul. 7, 1994, which is incorporated herein by reference. The method disclosed for preparing compound III is shown in Scheme 1. This method involves an urea bond forming coupling reaction of intermediates 1 and 2 in the presence of a catalyst such as 4-dimethylaminopyridine and the like to give ester 3. Ester hydrolysis of the valine carboxy protecting group (for example, lithium hydroxide hydrolysis) affords compound III. This process has the disadvantage of including the steps of carboxy protecting and then de-protecting the valine residue. A process that avoids protection and deprotection steps would be preferred. Therefore, there is a continuing need for an improved process for the preparation of III. ##STR4##
It has recently been discovered that III can be prepared by reacting amine 4 with carboxylic acid 5, without first protecting the carboxylic acid as the ester (see Scheme 2). Previously, processes for preparing N-acylated activated amino acid derivatives such as 5 typically resulted in the formation of significant amounts of side products such as dipeptides (5a) and acylated dipeptides (5b) (see Scheme 3). Therefore, there is a continuing need for an improved process for the preparation of N-acylated activated amino acid derivatives which will minimize the formation of these unwanted side products. ##STR5##